Process for preparing 4-chloro-3-hydroxybutanoic acid ester

ABSTRACT

The present invention relates to a process for preparing 4-chloro-3-hydroxybutanoic acid ester, an intermediate for preparing atorvastatin, in high purity and yield, by comprising the steps of 1) reacting epichlorohydrin of formula (2) with cyanide of formula (3) under the condition of pH ranging from 7 to 8, to form the 4-chloro-3-hydroxybutyronitrile of formula (4) and 2a) dissolving the 4-chloro-3-hydroxybutyronitrile of formula (4) in an alcoholic solvent and reacting it with hydrogen chloride, or 2b) reacting the 4-chloro-3-hydroxybutyronitrile of formula (4) in an alcoholic solvent saturated with hydrogen chloride, to form the 4-chloro-3-hydroxybutyronitrile acid ester of formula (I).

TECHNICAL FIELD

The present invention relates to a process for preparing4-chloro-3-hydroxybutanoic acid ester. More specifically, the presentinvention relates to a process for preparing 4-chloro-3-hydroxybutanoicacid ester of high optical and chemical purity in high yield through theoptimization of the reaction pH, addition order of reactants, and/oramounts, etc. of reaction solvent and the reactants.

BACKGROUND ART

4-Chloro-3-hydroxybutanoic acid ester of the following formula:

, wherein R is C₁₋₄alkyl,

is a useful intermediate for preparing atorvastatin, a therapeutic agentof hyper-lipidemia.

A process for preparing the above 4chloro-3-hydroxybutanoic acid ester,known in the art, comprises the following steps of:

1) reacting epichlorohydrin of the following formula:

with a cyanide of the following formula:M(CN)_(n)   (3)

, wherein M is a cation, and n is an integer of 1 to 3,

to form 4-chloro-3-hydroxybutyronitrile of the following formula:

2) subjecting the 4-chloro-3-hydroxybutyronitrile of the above formula(4) to acid hydrolysis to form the 4-chloro-3-hydroxybutanoic acid esterof the above formula (1).

The above process may be depicted by the following reaction scheme:

First, some processes to prepare 4-chloro-3-hydroxybutyronitrile instep 1) are known in the art: reacting chiral epichlorohydrin withliquid hydrogen cyanide under heating in a sealed container for severaldays [Hormann, Ber., 1879, 12, 23], employing hydrogen cyanide withpotassium cyanide as a catalyst [F. Binon, Bull. Soc. Chim. Belges.,1963, 72, 166], performing the reaction under the neutral condition bysimultaneously introducing a mixed aqueous solution of sodium cyanideand potassium cyanide with an aqueous solution of acetic acid [Culvenor,J. Chem. Soc., 1950, 3123], etc.

However, the Hormann's method employing liquid hydrogen cyanide is notsuitable for commercial production because liquid hydrogen cyanide isvery dangerous to handle, and it requires extremely long reaction timeand a specially designed pressure-resistant container for industrialuse. The Binon's method also has the same problem of using hydrogencyanide. Also, the Culvenor's method has difficulty to control the speedof simultaneous introduction of an aqueous metal cyanide solution withan acid solution to maintain the optimal pH.

In order to resolve the above-mentioned problems and to provide aneconomical process suitable for large-scale industrial production,various improved processes have been developed. For example, JapanesePatent No. 5310671 by Daiso Co., Ltd. in Japan discloses a processcharacterized by maintaining the reaction pH within the basic range of 8to 10 by simultaneously introducing an inorganic acid solution and anaqueous solution of alkali metal cyanide into an aqueous solution ofepichlorohydrin. This process tried to resolve such problems asformation of the side products of 3-hydroxyglutaronitrile and4-hydroxycrotonitrile under basic pH and elevated temperature, asdescribed in Org. Syntheses, CV 5, 614. However, it is not so easy toadjust pH by simultaneously introducing sulfuric acid solution and basicaqueous cyanide solution into the epichlorohydrin solution, andparticularly, the heat of neutralization occurred from simultaneousintroducing an acid and a base may be a concern in terms of the controlof the reaction temperature.

Subsequently, a process to prepare 4-chloro-3-hydroxybutanoic acid esterin step 2) comprises the steps of subjecting4-chloro-3-hydroxybutyronitrile to hydrolysis under aqueous acidicconditions to form a carboxylic acid (4-chloro-3-hydroxybutanoic acid),which was further transformed to 4-chloro-3-hydroxybutanoic acid ester.This process may be depicted by the following reaction scheme:

In the above reaction, R—C(OH)═NH is formed as an intermediate, andhydrolysis of the imine (═NH) forms a carboxylic acid. The reaction is aconventional hydrolysis employing an aqueous acid solution, and has suchproblems that it should be performed in the reflux temperature, andoften stops in the amide intermediate which can hardly be hydrolyzed.

Another known process (Finner's reaction) comprises the steps ofdissolving 4-chloro-3-hydroxybutyronitrile in an alcohol or a mixedsolution of an alcohol and an inert solvent, performing the reaction ata low temperature for a long time with blowing hydrogen chloride gasthereto to form an imidate as an intermediate, and hydrolyzing theimidate with an aqueous acid solution. The above process may be depictedby the following reaction scheme:

According to the process described in a literature by Geza Braun, J.Amer. Chem. Soc., 1930, 52, 3167, the reactants are cooled down in amixed solution of ethanol and ethyl ether, the reaction is performedwith an extreme excess of hydrogen chloride gas over several hours, andthe reaction mixture is concentrated and the residual hydrogen chloridegas is removed through distilling the solvent therefrom. An imidatecompound obtained from the above reaction is dissolved in water again,and hydrolyzed to obtain the desired ester compound. In this case, ifthe excessive hydrogen chloride is not removed, a carboxylic acid isformed as a byproduct with the ethyl ester, and thus, the concentrationshould be performed as completely as possible when distilling thesolvent under reduced pressure. For industrial application, the aboveprocess has several problems such that an anti-rust reactor should bevery carefully selected due to the presence of excessive hydrogenchloride and its productivity is very low due to an extremely longreaction time. In addition, the present inventors performed the reactionaccording to the above literature, and as a result, confirmed that thereaction has such inconveniences that an impurity with unknown structureis formed, and so the desired product of high purity can be obtainedonly after a purification process such as distillation, and the reactiontakes a long time of several days.

Therefore, in order to resolve the above problems and to provide aneconomical process suitable for large scale industrial production,various improved processes have been developed. For example, JapanesePatent No. 04124157 discloses a process for preparing4-chloro-3-hydroxybutanoic acid ester of high optical activity. Thisprocess provides 4-chloro-3-hydroxybutanoic acid ester with high opticalactivity by heating 4-chloro-3-hydroxybutyronitrile in a concentratedhydrochloric acid solution, extracting the solution to obtain4-chloro-3-hydroxybutanoic acid, and esterifying the isolated carboxylicacid with a small amount of an acid catalyst in an alcoholic solvent.According to the patent, 4-hydroxy-3-hydroxybutyronitrile is treatedwith concentrated hydrochloric acid and heated to obtain an aqueoussolution of 4-chloro-3-hydroxybutanoic acid. The resulting aqueoussolution is concentrated under reduced pressure and extracted with asolvent. The extract concentrate is purified with a columnchromatography, and then, reacted with a suitable alcohol under an acidcatalysis to afford 4-chloro-3-hydroxybutanoic acid ester. However, thisprocess is not suitable for practical application, either, in that theemployment of an extremely excessive amount of concentrated hydrochloricacid followed by concentration under reduced pressure may causecorrosion of apparatus. Moreover, the concentration of water employed asa reaction solvent under reduced pressure is not easy and further,several-times of repeated extractions of 4-chloro-3-hydroxybutanoic acidare required due to its good solubility into an aqueous phase.

DISCLOSURE OF THE INVENTION

The present inventors have performed extensive studies to resolve theabove described problems of the prior arts. As a result, the presentinventors found a certain optimal range of the reaction pH. Theinventors also found that the desired product with high optical activitycan be obtained in high purity and yield by switching the order ofaddition of reactants, and/or modifying kinds, amounts, etc. of areaction solvent and the reactants.

Therefore, the purpose of the present invention is to provide a processthat can prepare 4-chloro-3-hydroxybutanoic acid ester of high opticalactivity and purity in good yield, low cost, and high suitability forlarge scale operation.

One aspect of the present invention provides a process for preparing4-chloro-3-hydroxybutyronitrile of formula:

, comprising the step of

1) reacting epichlorohydrin of formula:

with a cyanide of formula:M(CN)_(n)   (3)

, wherein M is a cation, and n is an integer of 1 to 3,

under the pH condition ranging from 7 to 8, particularly from 7.3 to7.8, to form the 4-chloro-3-hydroxybutyronitrile of formula (4).

A second aspect of the present invention provides a process forpreparing 4-chloro-3-hydroxybutanoic acid ester of formula:

, wherein R is C₁₋₄alkyl,

comprising the step of

2a) dissolving 4-chloro-3-hydroxybutyronitrile of formula (4) in analcoholic solvent, and then, reacting it with hydrogen chloride, or

2b) reacting the 4-chloro-3-hydroxybutyronitrile of formula (4) in analcoholic solvent saturated with hydrogen chloride,

to form the 4-chloro-3-hydroxybutanoic acid ester of formula (1).

A third aspect of the present invention provides a process for preparing4-chloro-3-hydroxybutanoic acid ester of formula (1) comprising theabove step 1) and step 2a) or 2b).

Hereinafter, the present invention will be explained in detail.

1) Step 1): Preparation of 4chloro-3-hydroxybutyronitrile

The present inventors found that the composition of the reaction productvaries depending on the pH at which epichlorohydrin reacts with cyanide,as depicted in the following reaction scheme:

First, when the reaction solution is acidic, the ring-opening reactionof epichlorohydrin is accelerated by acid catalysis, to formconsiderable amounts of 3,4-dihydroxybutyronitrile and1,3-dichloroisopropanol, and their amounts increase as the aciditybecomes stronger.

Second, when the reaction solution is basic, the epoxy ring is attackedby cyanide, and thus, the desired 4-cyano-3-hydroxybutyronitrile isproduced as a main product, but hydroxyl anion formed during thereaction attacks the chloromethyl group intramolecularly to form anotherepoxy ring resulting in 3,4-epoxybutyronitrile, which is attacked againby cyanide group to form 3-hydroxyglutaronitrile. Alternatively,β-elimination reaction of 3,4-epoxybutyronitrile by the action of baseforms 4-hydroxycrotononitrile.

Therefore, as discovered by Daiso Co., Ltd., the present inventorsconfirmed that it is very important to adjust the pH of the reactionsolution. However, while Daiso Co., Ltd, reported that the pH in therange of 8 to 10 is the most preferable, the present inventors newlyfound that the formation of byproducts can be minimized and the reactioncan be performed most efficiently by adjusting the pH of the reactionsolution to the range of 7 to 8, particularly 7.3 to 7.8. Moreover,since it is not easy to simultaneously introduce the two reactants, oneof which is acidic and the other is basic, with delicately maintainingthe reaction pH within a certain range, the present inventors developeda process that can very strictly control the conditions of the reaction,by switching the order of addition of the reactants in step 1).

Specifically, in the present invention, metal cyanide and an inorganicacid are introduced into a reactor and the pH is adjusted to the desiredrange. Subsequently, epichlorohydrin is added thereto to carry out thereaction under the condition in which the pH is controlled in arelatively simple manner. That is, the pH of the reaction solution isadjusted to 7.0 to 8.0, preferably 7.3 to 7.8, and then, epichlorohydrinis added thereto dropwise.

The kinds of metal cyanide used for the above process include an alkalimetal cyanide such as sodium cyanide, potassium cyanide, etc., calciumcyanide, barium cyanide and the like, but sodium cyanide and potassiumcyanide are particularly preferable because they are readily availableand have been widely used in the industry. The kinds of inorganic acidintroduced for adjusting the pH include hydrochloric acid, nitric acid,sulfuric acid, sulfonic acid, phosphoric acid, methanesulfonic acid,etc. Preferable are sulfonic acid, sulfuric acid and hydrochloric acid.

The reaction with the inorganic acid may be preformed in a mixture ofalcohol and water, or water, and preferably, in water, and water may beused in the weight ratio of 2 to 20 based on the weight ofepichlorohydrin. However, considering stirring efficiency and economicalaspect, it is preferable to use water in the weight ratio of 3 to 6,more preferably 3 to 4. The reaction temperature may be in the range of0 to 90° C., but the temperature range of 10 to 40° C. is preferable tomaintain reasonable reaction rate, and to suppress the formation ofbyproducts. Particularly, the temperature range of 15 to 25° C. is themost preferable.

Upon completion of the reaction, salt compound formed therefrom may befiltered depending on the kinds of metal cyanide and acid introducedinto the reaction solution, and the filtrate is extracted with anorganic solvent, and the extract is concentrated to obtain the desired4-chloro-3-hydroxybutyronitrile. The suitable kinds of extractionsolvent include toluene, butanol, ethyl acetate, butyl acetate,dichloromethane, etc. In terms of extracting capacity, ethyl acetate,butyl acetate, butanol, dichloromethane, etc. are preferable, and ethylacetate and dichloromethane are more preferable.

2) Step 2): Preparation of 4-chloro-3-hydroxybutanoic acid ester

In this step, the present inventors tried to employ minimal amount ofacid and to omit a step of extracting 4-chloro-3-hydroxybutanoic acid asan intermediate, and simultaneously, to obtain the desired product inhigh purity and yield for a shortened period of time. As a result, thepresent inventors found that the desired carboxylic acid ester can berapidly prepared in high purity by dissolving4-chloro-3-hydroxybutyronitrile in an alcoholic solvent and bubblinghydrogen chloride gas thereto. Also, the same reaction profiles could beobtained by using an alcoholic solvent preliminarily saturated withhydrogen chloride gas.

The alcoholic solvent used in this step may be C₁₋₄alcohol. It may beused alone, or used in combination with another solvent. In that case,diethyl ether or diisopropyl ether is preferable as co-solvent. Mostpreferably, the alcoholic solvent is used alone. The weight-by-weightratio of the alcohol to 4-chloro-3-hydroxybutyronitrile may be in therange of 1 to 10, preferably 1.5 to 4, more preferably 1.5 to 2.5, interms of economical efficiency and reaction rate.

The amount of hydrogen chloride may be in the range of 1 to 10 moleequivalents, preferably 1 to 6 mole equivalents, for a fast reaction andwork-up of the residual hydrogen chloride. The reaction temperature maybe in the range of 0 to 80° C., preferably 15 to 50° C., more preferably15 to 25° C., considering the purity of reaction. In case that opticallyactive epichlorohydrin is used as the starting material,4-chloro-3-hydroxybutanoic acid ester obtained from the above reactionretains the optical purity.

In addition, upon completion of the reaction, the present invention hasthe advantage to increase the productivity by reducing the steps ofreaction through using relatively very small amount of alcoholic solventwhich enables direct extraction with an organic solvent withoutconcentration of alcoholic solvent, while excess alcoholic solvent wasdistilled under reduced pressure in the prior art.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be more specifically illustrated by thefollowing examples. However, the following examples should not beconstrued as limiting the scope of the present invention in any way.

EXAMPLE 1 Preparation of 4-chloro-3-hydroxybutyronitrile (NaCN/H₂ SO₄)

Sodium cyanide (9.93 g) was dissolved in 60 ml of distilled water, andthe solution was cooled down in ice bath. To this solution was addeddropwise sulfuric acid of 9.87 g while maintaining the temperature to20° C. or lower, and the pH was measured and confirmed to be 7.7. To theabove solution was added 15 g of epichlorohydrin, and then, the mixturewas stirred at room temperature. Upon completing the reaction, thereaction solution was extracted three times with ethyl acetate, andconcentrated under reduced pressure to obtain 17.2 g (yield: 89%) of thetitle compound as deep yellow oil. Chemical purity (GC): 96.5%

¹H-NMR (CDCl₃) δ 4.21 (1H, m), 3.66 (2H, d, J=5.6 Hz), 3.03 (1H, d,J=5.6 Hz, —OH), 2.73 (2H, m)

¹³C-NMR (CDCl₃) δ 117.1, 67.3, 47.3, 23.3

EXAMPLE 2 Preparation of 4-chloro-3-hydroxybutyronitrile (KCN/H₂ SO₄)

The title compound of 17.8 g (yield: 92%) was obtained according tosubstantially the same method as in Example 1 except using potassiumcyanide instead of sodium cyanide. Chemical purity (GC): 96.7%

EXAMPLE 3 Preparation of 4-chloro-3-hydroxybutyronitrile (KCN/HCl)

The title compound of 17.4 g (yield: 90%) was obtained according tosubstantially the same method as in Example 1 except using potassiumcyanide instead of sodium cyanide and concentrated hydrochloric acidinstead of sulfuric acid. Chemical purity (GC): 95.8%

EXAMPLE 4 Preparation of 4-chloro-3(S)-hydroxybutyronitrile (KCN/H₂SO₄)

The title compound of 17.6 g (yield: 91%) was obtained according tosubstantially the same method as in Example 1 except using potassiumcyanide instead of sodium cyanide and (S)-epichlorohydrin asepichlorohydrin. Chemical purity (GC): 96.5%; Optical purity (HPLC):99.2% ee

EXAMPLE 5 Preparation of 4-chloro-3-hydroxybutanoic acid ethyl ester

Ethanol was cooled down, and anhydrous hydrogen chloride gas was bubbledslowly thereto. The obtained solution was titrated to prepare 10 Nethanol solution of hydrogen chloride. The ethanol solution of hydrogenchloride of 30 ml was mixed with 11.96 g of4chloro-3-hydroxybutyronitrile, and the reaction was performed whileheating to 60° C. under nitrogen atmosphere. Upon completing thereaction, the reaction solution was cooled down, and extracted with 30ml of distilled water and 50 ml of ethyl acetate, and the aqueous phasewas further extracted twice with 50 ml of ethyl acetate. The extract wascollected and concentrated under reduced pressure to obtain the titlecompound of 15.5 g (yield: 93%). Chemica purity (GC): 96.8%

¹H-NMR (CDCl₃) δ 4.20˜4.30 (1H, m), 4.18 (2H, q, J=7.3 Hz), 3.55˜3.65(2H, m), 3.17 (1H, br), 2.55˜2.70 (2H, m), 1.28 (3H, t, J=7.3 Hz)

¹³C-NMR (CDCl₃) δ 171.8, 68.0, 61.0, 48.2, 38.5, 14.1

EXAMPLE 6 Preparation of 4-chloro-3-hydroxybutanoic acid methyl ester

The title compound of 15.8 g (yield: 95%) was obtained according tosubstantially the same method as in Example 1 except using4-chloro-3(S)-hydroxybutyronitrile as 4-chloro-3-hydroxybutyronitrileand methanol instead of ethanol. Chemical purity (GC): 97.1%; Opticalpurity (HPLC): 99.2% ee

¹H-NMR (CDCl₃) δ 4.28 (1H, m), 3.70 (3H, s), 3.61 (2H, m), 3.40 (1H,br), 2.65 (2H, m)

¹³C-NMR (CDCl₃) δ 172.2, 68.0, 52.0, 38.2, 38.8

INDUSTRIAL APPLICABILITY

According to the present invention, 4-chloro-3-hydroxybutyronitrile ofhigh purity can be obtained in high yield by reacting epichlorohydrinwith cyanide at the pH range of 7 to 8, particularly, 7.3 to 7.8,preferably by adjusting the pH to the above range by preliminarilymixing aqueous metal cyanide with an inorganic acid at room temperatureand room pressure, and then, adding epichlorohydrin thereto to performthe reaction. Also, 4-chloro-3-hydroxybutyronitrile with high opticalactivity can be obtained with using chiral epichlorohydrin. Moreover,4-chloro-3-hydroxybutanoic acid ester can be prepared on a large scalein high purity and yield through one-step reaction from4-chloro-3-hydroxybutyronitrile. Further, from4-chloro-3-hydroxybutyronitrile with optical activity,4-chloro-3-hydroxybutanoic acid ester retaining the optical activity canbe obtained in high yield and purity.

1. A process for preparing 4-chloro-3-hydroxybutyronitrile of formula:

comprising the step of 1) reacting epichlorohydrin of formula:

with a cyanide of formula:M(CN)_(n)   (3), wherein M is a cation, and n is an integer of 1 to 3,under the condition of pH ranging from 7 to 8, to form the4-chloro-3-hydroxybutyronitrile of formula (4).
 2. A process forpreparing 4-chloro-3-hydroxybutanoic acid ester of formula:

wherein R is C₁₋₄alkyl, comprising the step of 2a) dissolving4-chloro-3-hydroxybutyronitrile of formula:

in an alcoholic solvent, and then, reacting it with hydrogen chloride,or 2b) reacting the 4-chloro-3-hydroxybutyronitrile of formula (4) in analcoholic solvent saturated with hydrogen chloride, to form the4-chloro-3-hydroxybutanoic acid ester of formula (1).
 3. A process forpreparing 4-chloro-3-hydroxybutanoic acid ester of formula:

wherein R is C₁₋₄alkyl, comprising the step of 2a) dissolving4-chloro-3-hydroxybutyronitrile of formula:

in an alcoholic solvent, and then, reacting it with hydrogen chloride,or 2b) reacting the 4-chloro-3-hydroxybutyronitrile of formula (4) in analcoholic solvent saturated with hydrogen chloride, to form the4-chloro-3-hydroxybutanoic acid ester of formula (1), comprising thesteps of: 1) reacting epichlorohydrin of formula:

with a cyanide of formula:M(CN)_(n)   (3), wherein M is a cation, and n is an integer of 1 to 3,under the condition of pH ranging from 7 to 8, to form the4-chloro-3-hydroxybutyronitrile of formula (4), under the condition ofpH ranging from 7 to 8, to form 4-chloro-3-hydroxybutyronitrile offormula:

2a) dissolving 4-chloro-3-hydroxybutyronitrile of formula (4) in analcoholic solvent, and then, reacting it with hydrogen chloride, or 2b)reacting 4-chloro-3-hydroxybutyronitrile of formula (4) in an alcoholicsolvent saturated with hydrogen chloride, to form the4-chloro-3-hydroxybutanoic acid ester of formula (1).
 4. The process ofclaim 1, wherein the pH is adjusted in the range of 7.3 to 7.8.
 5. Theprocess of claim 1, wherein the pH is adjusted by adding an inorganicacid to the cyanide solution, and then, epichlorohydrin is addedthereto.
 6. The process of claim 5, wherein the inorganic acid isselected from the group consisting of hydrochloric acid, nitric acid,sulfuric acid, sulfonic acid, and phosphoric acid.
 7. The process ofclaim 6, wherein the inorganic acid is sulfuric acid or concentratedhydrochloric acid.
 8. The process of claim 1, wherein the cyanide issodium cyanide or potassium cyanide.
 9. The process of claim 2, whereinthe alcoholic solvent is methanol or ethanol.
 10. The process of claim2, wherein the hydrogen chloride is anhydrous hydrogen chloride gas. 11.The process of claim 2, wherein the weight-by-weight ratio of thealcoholic solvent to 4-chloro-3-hydroxybutyronitrile is in the range of1.5:1 to 2.5:1.
 12. The process of claim 1, wherein epichlorohydrin or4-hydroxybytyronitrile has optical activity.
 13. The process of claim 3,wherein the pH is adjusted in the range of 7.3 to 7.8.
 14. The processof claim 3, wherein the pH is adjusted by adding an inorganic acid tothe cyanide solution, and then, epichlorohydrin is added thereto. 15.The process of claim 3, wherein the cyanide is sodium cyanide orpotassium cyanide.
 16. The process of claim 3, wherein the alcoholicsolvent is methanol or ethanol.
 17. The process of claim 3, wherein thehydrogen chloride is anhydrous hydrogen chloride gas.
 18. The process ofclaim 3, wherein the weight-by-weight ratio of the alcoholic solvent to4-chloro-3-hydroxybutyronitrile is in the range of 1.5:1 to 2.5:1. 19.The process of claim 2, wherein epichlorohydrin or4-hydroxybytyronitrile has optical activity.
 20. The process of claim 3,wherein epichlorohydrin or 4-hydroxybytyronitrile has optical activity.